The accepted medical characterization and definition for women of an age inclusive of periodically recurring menstrual cycles, of the syndrome commonly is referred to as premenstrual tension syndrome. PMS is a group of symptoms that occur together almost entirely or principally during the intermittent luteal phase of a menstrual cycle; those intermittent periodic luteal phase-occurring symptoms that characterize a PMS abnormality, are a plurality of at least two or more (normally many) of physical, psychological and/or behavioral symptoms of combined substantially incapacitating severity to an extent requiring treatment in order for the affected woman-subject to continue to function normally socially and/or occupationally of conventional daily activities during that luteal phase.
The periodic intermittently reoccurring symptoms of PMS match the phases of a woman's menstrual cycle, occurring normally and principally in the menstrual cycle's luteal phase which by medical definition occurs after ovulation with PMS symptoms normally beginning at, or near the end of or shortly after the follicular (egg development) stage and lasting to about the beginning of the menses (bleeding) stage of the menstrual cycle.
As shall be more particularly pointed out below, the method of the present invention of PMS treatment utilizes solely and exclusively angiotensin II subtype 1 (AT1) antagonists, and the foregoing noted prior art of the U.S. Pat. No. 5,246,943 to Blankley, et. al does not apply nor even refer to the presence of the AT1 receptors located in the subfornical organ (SFO), organism vasculosum of the lamina terminalis, median preoptic nucleus, nucleus of the solitary tract, the area postrema nucleus of the hypothalamus and ventral hippocampus which contain almost exclusively AT1 receptors. (Rowe, B. P. et. al. "Analyses of Angiotensin II Receptor Subtypes in Individual Rat Brain Nuclei, Neuroendocrinology: 1992;55:563-573). In addition, the Blankley et. al. patent states that their interest is to treat the aspect of PMS described as the "disorder of excessive water retention" and therefore does not refer to the premenstrual syndrome of multiple physical psychological and/or behavioral symptoms as described briefly above and to be further elucidated subsequently. Apart from that, The Conn's Current Therapy., Premenstrual Syndrome above-noted, at Page 1016 thereof, column 1 at the last paragraph explicitly states that no consistent relief appears to be provided by "diuretics", a class of drugs known to promote the loss of water.
U.S. Pat. No. 5,246,943 granted Sep. 21, 1993 to Blankley, et. al. discloses a series of angiotensin antagonists directed at the subtype 2 receptors, and is directed only at symptoms mediated by these receptors in the central nervous system. Accordingly, the Blankely, et. al., U.S. Pat. No. 5,246,943 has no relevance to and clearly does not suggest nor make logical the present invention relating to PMS symptoms divergent and not in the least comparable to those described in the aforestated patent, which is directed at AT2 receptors in the CNS and limited in its meaning having no reasonable common basis with menstrual luteal phase PMS symptoms intermittently recurring and associated directly with the luteal phase and regulated as will be described to areas of the CNS containing angiotensin II subtype 1 receptors (AT1). Important is the medically recognized fact that PMS is strictly associated with recurring menstrual cycles and the appearance of PMS symptoms solely and exclusively during the luteal phase. Moreover, it has been experimentally established that such PMS symptoms disappeared when human females were ovariectomized, evidence in a study by R. F. Casper and Hearn. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am. J. Obstet. Gynecol. 162:105-9, 1990, and evidenced by females who underwent medical "ovariectomy" by use of a GnRH agonist, which effectively eliminated their menstrual cycle as demonstrated by Muse, K. N., et al. The premenstrual syndrome: effects of "Medical Ovariectomy", N. Engl. J. Med. 311:1,345, 1984. Accordingly, the drug of the present invention, acting AT1) receptors in the CNS and outside the central nervous system (peripherally) and directed to strictly female menstrual cycle's luteal phase of "numerous" (multiple) concurrent PMS symptoms of which perhaps one of numerous required symptoms (in order to be characterized as PMS syndrome) might or might not be present, does "not" embody any suggestion or teaching that would suggest obviousness of the present invention.